OFQ, a heptadeca peptide, has been isolated from rat brain and is a natural ligand to a G-protein coupled receptor (OFQ-R), found at high levels in brain tissue. OFQ exhibits agonistic activity at the OFQ-R both in vitro and in vivo.
Julius (Nature 377,476, [1995]) discusses the discovery of OFQ noting that this peptide shares greatest sequence homology with dynorphin A, an established endogenous ligand for opioid receptors. OFQ inhibits adenylate cyclase in CHO(LC 132.sup.+) cells in culture and induces hyperalgesia when administered intra-cerebroventricularly to mice. The pattern of results indicate that this heptadecapeptide is an endogenous agonist of the LC 132 receptor and it appears to have pro-nociceptive properties. It has been described that when injected intra-cerebroventricularly in mice, OFQ slowes down locomotive activity and induces hyperalgesia and it has been concluded that OFQ may act as a brain neurotransmitter to modulate nociceptive and locomotive behavior.
It has been found that the compounds of the present invention interact with the orphanin FQ (OFQ) receptor and consequently are useful in the treatment of a variety of psychiatric, neurological and physiological disorders.
In the following references some of these indications have been described:
Nociceptin/orphanin FQ and the opioid receptor-like ORL1receptor, Eur. J. Pharmacol., 340: 1-15, 1997;
The orphan opioid receptor and its endofenous ligand ociceptin/orphanin FQ, Trends Pharmacol. Sci., 18:293-300,1997;
Orphanin FQ is a functional anti-opioid peptide, Neuroscience, 75:333-337, 1996;
Orphanin FQ/nociceptin-lack of antinociceptive, hyperalgesic or allodynic effects in acute thermal or mechanical tests, following intracerebroventricular or intrathecal administration to mice or rats, Eur. J. pain, 2: 267-280, 1998;
Orphanin FQ acts as an anxiolytic to attenuate behavioral responses to stress, Proc. Natl. Acad. Sci., USA, 94: 14854-14858, 1997;
Orphanin FQ, an agonist of orphan opioid receptor ORL1, stimulates feeding in rats, Neuroreport, 8: 369-371, 1996;
Facilitation of long-term potentiation and memory in mice lacking nociceptin receptors, Nature, 394: 577-581, 1998;
Distribution of nociceptin/orphanin FQ receptor transcript in human central nervous system and immune cells, J. Neuroimmuno, 81: 184-192, 1998;
Orphanin FQ plays a role in sepsis, Prog. Clin. Biol. Res. (1998), 397, 315-325.
Objects of the present invention are the compounds of formula I and pharmaceutically acceptable addition salts thereof, racemic mixtures and their corresponding enantiomers, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred above, or in the manufacture of corresponding medicaments.